8 Aug 2007
Researchers at Cleveland Clinic have identified the region within high density lipoprotein (HDL), the major carrier of "good" cholesterol, that can become dysfunctional within the artery wall, inhibiting the body's ability to fight cholesterol buildup.
The work of the researchers led by Stanley Hazen, M.D., Ph.D., Head of the Section of Preventive Cardiology and Rehabilitation at Cleveland Clinic appears online Aug. 5 in the journal Nature Structural & Molecular Biology in a paper entitled "The Refined Structure of Nascent HDL Reveals a Key Functional Domain for Particle Maturation and Dysfunction." It builds upon the researchers' previous work which determined that not all HDL helps protect arteries from becoming clogged with fatty deposits.
The findings are important because raising HDL levels represents a major target for new treatment strategies of atherosclerosis, the accumulation of harmful plaque in the arteries, by the pharmaceutical industry. Yet it appears that the function as well as the level of the HDL is important. This may also help explain research earlier this year which found that despite raising the level of HDL (good) cholesterol, the drug torcetrapib did not slow the progression of artery disease.
"In this study we describe a refined molecular model of a nascent HDL molecule that is dramatically improved upon its predecessors," Dr. Hazen said. "With our enhanced detail of the HDL molecule structure we are better able to understand the location and mechanics of dysfunction in HDL.
HDL becomes dysfunctional when a specific region on HDL is modified by myeloperoxidase (MPO), an enzyme present in white blood cells and found in atherosclerotic plaque. This inhibits HDL's ability to mature and effectively carry cholesterol cargo from cells of the artery wall. In their paper, the researchers describe the HDL as having a "solar flare" structure.
Zhiping Wu, Ph.D., a research fellow at Cleveland Clinic is the paper's first author. Valentin Gogonea, Ph.D., an Associate Professor in the Department of Chemistry at Cleveland State University collaborated in the research.